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Antipsychotic medications are a necessary treatment for individuals with psychoses. To be maximally beneficial, they must have an acceptable side effect profile and be taken as prescribed (1). Unfortunately, a recent review suggests that 40% to 80% of patients taking antipsychotic medication experience weight gain that exceeds ideal body weight by 20% or greater (2). Obesity and weight gain have been associated with hypertension, type II diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some types of cancer (3,4). Moreover, obesity is common in schizophrenia (3), including an increased risk for certain obesity-related conditions such as type II diabetes and cardiovascular disease (4–6). It appears from the literature that the greatest weight gain is experienced on clozapine and olanzapine, then on risperidone and quetiapine; less data are available for ziprasidone (1,7,8). Many theories have been advanced to explain this antipsychotic-induced weight gain (9,10). Recently, serotonin (5-HT2c), dopamine (D2), and histamine (H1) receptor blockade have been implicated (2,8). It has been reported that psychotropic drugs that influence serotonin (5-HT) neurotransmission affect food intake and cause fluctuations in weight. If they facilitate serotonin transmission, the result is reduced food consumption and weight loss, and if they block serotonin transmission then this leads to increased food intake and weight gain; however, this remains speculative (8). There are several issues of concern. First, weight gain may cause those taking antipsychotics to discontinue their medications, thus predisposing them to relapse (1). This has not been supported (7,11,12). Second, although weight gain may reach a plateau after a certain period, the results are mixed as to whether this may be after a relatively short or longer period of time (7,8,13). Third, some studies indicate that weight gain is highest in individuals with a low baseline body mass index (BMI) (1,11,14); others have failed to find such an association (8,15). Finally, it has been suggested that weight gain is dosage related. This was not confirmed with olanzapine (16,17) or with quetiapine (18). One of the reasons for such mixed results may be that the quality of the data does not allow for clear conclusions to be drawn (7). Few studies give percentage changes; there are few well conducted trials comparing individual medications, and much information comes from short-term trials (7). Weight gain from these agents may be a particular problem for adolescents (13,15,17,19), who are more sensitive to issues of body image and self-esteem, making the problem particularly serious for young people experiencing their first episode of psychosis. Recent interest in early intervention is driven by many excellent goals, some of which are related to self-esteem, adaptation, and encouraging adherence to medication. The purpose of this study is to examine weight gain in a sample that is engaged in comprehensive treatment in an early psychosis program (20). This is a naturalistic study examining individuals who are receiving optimal psychosocial interventions and low-dosage, second-generation antipsychotics. Our questions were:
MethodSubjects In terms of medications, 43 were on olanzapine and 32 were on risperidone throughout the first year; 29 switched between olanzapine, risperidone, and quetiapine; and 7 were switched to clozapine and 3 to depots from olanzapine, risperidone, or quetiapine. Concomitant medication was recorded, but weight was not measured in sequence with stopping and starting these medications. Anticholinergic use was minimal and after the initial assessment was less than 1%. Antidepressant use was significant: it was used in up to 27% but consisted almost exclusively of selective serotonin reuptake inhibitors (SSRIs). Anxiolytics, predominantly benzodiazepines and nonbenzodiazepine hypnotics, were prescribed in 4% to 8% at different assessment periods. Measures Figure 1 Body mass index (BMI) classifications at each assessment  ResultsSubjects had an average BMI of 24.47 (SD 4.69) at the initial assessment. Over the course of the year, these individuals gained an average of 11.97% of their original body weight. They gained more weight in the first 6 months (increase in body mass [M] = 9.02%) than in the second 6 months (M = 2.95%). Initially, 35.9% of the sample were overweight or obese (22). This number rose to 57.9% at the 6-month follow-up and 59.7% at 1-year follow-up (Figure 1). A repeated-measures analysis of variance (ANOVA) was conducted to examine increases in BMI over time and sex differences. The model was significant (F = 43.28; df 2, 111; P < 0.001). As the assumption of sphericity was violated, reported values reflect the Greenhouse–Geiser correction. There was no effect of sex. There was a significant increase in BMI over time (F = 60.06; df 1.56, 174.91; P < 0.001). BMIs at each of the assessments were significantly different from all other assessments (Figure 2). Figure 2 BMI increases over time  Follow-up contrasts indicated significant linear (F = 73.36; df 1, 112; P < 0.001) and quadratic trends (F = 16.95; df 1, 112; P < 0.001). BMIs increased most from initial to 6-month follow-up assessments. To examine the effect of initial BMI category and sex on percentage of weight gained, a 1-way ANOVA was conducted. The model was significant (F = 2.35; df 5, 108; P < 0.05). There was no main effect of sex. There was a main effect of initial BMI classification on amount of weight gained (F = 4.04; df 2; 108, P < 0.05). This effect was moderated by a significant sex-by-BMI classification interaction (F = 3.73; df 2, 108; P < 0.05). For men, there was no effect of initial BMI classification. For women, there was a significant effect of initial BMI classification on percentage of weight gained (F = 3.46; df 2, 32; P < 0.05). Post hoc tests revealed that women starting with a normal BMI gained a significantly higher percentage of body weight (M = 17.78%) than women starting with an overweight BMI (M = 2.06%) (Figure 3). Figure 3 Mean percent weight gain by sex and BMI  DiscussionIn this sample of young first-episode patients, we see significant weight gain. There is, on average, a 12% increase in weight in the first year. The number of overweight or obese individuals increases from 36% to 60%. This is in contrast to the fact that, in Canada, 37.4% of persons aged 20 to 34 years are overweight or obese (23). Most of the increase occurs in the first 6 months, although it does continue up to 1 year. Normal weight women gained significantly more weight than overweight women. This was not true for men. This gain occurred even though patients were informed about potential weight gain and advised to increase their exercise and limit food intake. Limitations of this study are that we are unable to comment on either the differential effects of different compounds or of dosing on weight gain. These questions could only be addressed by randomized controlled studies. Concomitant medication use was recorded, but weight was not assessed at the times of starting and stopping. Concomitant medication use was not considered to significantly affect weight gain since this is not a side effect of selective serotonin reuptake inhibitors (SSRIs), the only category prescribed in more than 8% of cases. There are 2 implications of this study. First, weight gain occurred with all medications, despite information at the start that these medications caused weight gain and despite encouragement to exercise more and reduce food intake. Clinicians work with patients to find an optimal medication for each person. While reasons for switching were not systematically collected, side effects and patient requests are the common reasons. Second, based on recent National Institutes of Health clinical guidelines on obesity (24) that cite research showing significant increases in morbidity beyond a BMI of 25 and mortality beyond a BMI of 30 (25), many of these young individuals experiencing a first episode of psychosis are at a health risk. Some existing data suggest that short-term weight loss is achievable in a population with schizophrenia (2). However, to be successful, careful attention to design of the program is essential, and new innovative approaches to achieve long-term weight loss are necessary. This is not different from the situation in the general population (26). Weight-loss programs that aim to change lifestyle must be appropriate for the population being treated. It is reasonable to presume that lifestyle interventions for individuals with psychotic illnesses must be adapted to be effective in this population (27,28) and to take into account in their design such difficulties as cognitive deficits (29). A recent review suggested that the use of pharmacologic treatments of obesity with this population is problematic (2). The review found that agents for the treatment of obesity increase noradrenergic, dopaminergic, and serotonergic activity, which may exacerbate psychotic symptoms; no controlled clinical trials have been conducted with persons with schizophrenia. The potential of amantadine in pharmacologic treatment specifically for neuroleptic-induced weight gain has begun to be explored, but this is not a generally accepted treatment at this time (2). Thus, a pragmatic approach based upon the Canadian Guide to Clinical Preventive Health Care suggests that monitoring weight and BMI is appropriate in the first-episode population (30,31). Further, according to a recent periodic health examination update, “there is insufficient evidence to recommend for or against weight reduction therapy in obese adults without obesity related disease” (26, p 522). References1. Allison DB, Mentore JL, Moonseong H, Chandler LP, Cappelleri JC, Infante MC, and others. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 1999;60:215–20. 2. Green A, Patel JK, Goisman RM, Allison DB, Blackburn G. Weight gain from novel antipsychotic drugs: need for action. Gen Hosp Psychiatry 2000;22:224–35. 3. Allison DB, Mentore JL, Moonseong H, Chandler LP, Cappelleri JC, Infante MC, and others. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686–96. 4. Centers for Disease Control. Update: Prevalence of overweight among children, adolescents, and adults—United States, 1988–1994. MMWR Morb Mortal Week Rep 1997;46:198–202. 5. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960–1991. JAMA 1994;272:238–9 6. Tsuang MT, Perkins K, Simpson JC. Physical diseases in schizophrenia and affective disorder. J Clin Psychiatry 1993;44:4–6. 7. Taylor DM, McAskill R. Atypical antipsychotics and weight gain: a systematic review. Acta Psychiatr Scand 2000;101:416–32. 8. Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, and others. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358–63. 9. Doss FW. The effect of antipsychotic drugs on body weight: a retrospective review. J Clin Psychiatry 1979;40:528–30. 10. Stanton JM. Weight gain associated with neuroleptic medication: a review. Schizophr Bull 1995;21:463–72. 11. Beasley CM, Tollefson GD, Tran PV. Safety of olanzapine. J Clin Psychiatry 1997;58(Suppl 10):1–7. 12. Tollefson GD, Beasley CM, Tran PV, Street JS, Krueger JA, Tamura RN, and others. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457–65. 13. Van Bruggen MJ, Linszen DH, Dingemans PM, Lenior ME. A long term comparison of olanzapine and risperidone on weight gain as side effect in adolescents with recent onset schizophrenia. Schizophr Res 2001;49:290. 14. Umbricht DS, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994;55(Suppl B):157–60. 15. Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M. Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992;149:68–72. 16. Basson BR, Kinon BJ, Taylor CC, Szymanski KA, Gilmore JA, Tollefson GD. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 2001;62:23–8. 17. Kelly DL, Conley RR, Horn DS, Ushchak CM. Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months. J Child Adolesc Psychopharmacol 1998;8:15–9. 18. Brecher M, Rak IW, Melvin K, Jones AM. The long-term effect of quetiapine (SeroquelTM) monotherapy on weight in patients with schizophrenia. Int J Psychiatr Clin Pract 2000;4:287-91. 19. Wetterling T, Mubigbrodt H. Weight gain: side effect of atypical neuroleptics? J Clin Psychopharmacol 1999;19:316-21. 20. Addington J, Addington D. Early intervention for psychosis: the Calgary early psychosis treatment and prevention program. CPA Bulletin 2001;33:11-6. 21. Larsen TK, McGlashan TH, Moe LC. First-episode schizophrenia: early course parameters. Schizophr Bull 1996;22:241-56. 22. Statistics Canada. Health indicators. Volume 3. Ottawa (ON): Statistics Canada; 2001. http://www.statcan.ca/english/freepub/82B221-XIE/01201/defin1.htm. 23. Statistics Canada. Canadian Community Health Survey, version 1.1. Ottawa (ON): Statistics Canada; 2001. http://www.statcan.ca/english/sdds/3226.htm. 24. National Institutes of Health National Heart Lung and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Bethesda (MD): U.S. Department of Health and Human Services; 1998. 25. National Institutes of Health National Heart Lung and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evidence report. Obes Res 1998;6(Suppl 2):51S–209S. 26. Douketis JD, Feightner JW, Attia JA, Feldman WF. Periodic health examination, 1999 update: 1. Detection, prevention and treatment of obesity. CMAJ 1999;160:513–25. 27. Addington J. Group treatment for smoking cessation in schizophrenia. Psychiatr Serv 1998;49:92–8. 28. Addington J, El-Guebaly N. Group treatment for substance abuse in schizophrenia. Can J Psychiatry 1998;43:84–5 29. Addington J, Addington D. Neurocognitive and social functioning in schizophrenia. Schizophr Bull 1999;25:173–83. 30. Beaulieau MD. Screening for diabetes mellitus in the non pregnant adult. In: Report of the Canadian Task Force on the Periodic Health Examination. Ottawa (ON): Minister of Supply and Services Canada 1994; p 602–9. 31. Logan AG. Lowering the blood total cholesterol level to prevent coronary heart disease. In: Report of the Canadian Task Force on the Periodic Health Examination. Ottawa (ON): Minister of Supply and Services Canada; 1994; p 650–69. Author(s)Manuscript received May 2002, revised, and accepted November 2002. 1. Associate Professor, Department of Psychiatry, University of Toronto, Toronto, Onatrio; Associate Professor, Departments of Psychiatry and Psychology, University of Calgary, Calgary, Alberta. 2. Doctoral Candidate, Clinical Psychology Program, University of Calgary, Calgary, Alberta. 3. Professor and Chair, Department of Psychiatry, University of Calgary, Calgary, Alberta. Address for correspondence: Dr Jean Addington, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8 e-mail: jean_addington@camh.net
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